Ectoparasiticidal methods

ABSTRACT

The invention provides an ectoparasiticidal formulation which comprises an ectoparasiticidal agent, preferably fipronil, as the pesticidally-active ingredient, together with a crystallization inhibitor selected from the group consisting of alkyl-substituted pyrrolidones, and optionally, one or more organic solvents and/or co-solvents. Preferably, the crystallization inhibitor is N-octyl pyrrolidone, and the organic solvent, if present, preferably comprises diethylene glycol monoethyl ether. The ectoparasiticidal formulation surprisingly yields a significantly enhanced speed of kill. Methods for manufacturing the formulation, as well as methods for treating animals infested with ectoparasites, are also disclosed.

REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §119(e) of priorco-pending U.S. Provisional Patent Application Ser. No. 61/812,905,filed Apr. 17, 2013.

TECHNICAL FIELD

The present invention relates broadly to compositions and methods fortreating animals infested with parasites, and in particular, to topicalcompositions useful for treating companion animals infested with commonectoparasites. More specifically, this invention relates to improvedectoparasiticidal compositions for treating household pets infested withfleas, to methods of using the same, and to methods for preparing thesame.

BACKGROUND OF THE INVENTION

The infestation of companion animals, and in particular household petssuch as dogs and cats, with ectoparasites such as fleas, ticks and thelike, which live by hematophagy (i.e., by sucking the animal's blood),is highly undesirable. The prior art has developed numerous ready-to-usetopical formulations and compositions for treating such infestations,many of which are “spot on” or “pour on” formulations that are appliedby deposition on the animal's skin, and which contain an N-phenylpyrazole, and in particular,1-[2,6-Cl₂-4-CF₃-phenyl]-3-CN-4-[SO—CF₃]-5-NH₂-pyrazole, whose commonname is fipronil, as the active ingredient. Fipronil is an insecticidethat is particularly effective to control and/or eliminate adult fleasand ticks, and when applied topically, is acceptably safe for use oncompanion animals such as dogs and cats.

U.S. Pat. No. 6,395,765 to Etchegaray, which is incorporated herein byreference in its entirety, discloses and claims particularectoparasiticidal compositions comprising (a) an N-phenyl pyrazole, suchas fipronil, as the active ingredient, along with inert, inactiveingredients including (b) a crystallization inhibitor, (c) an organicsolvent, and (d) an organic co-solvent. A variety of specificcrystallization inhibitors, organic solvents and organic co-solvents aredisclosed.

In particular, the preferred crystallization inhibitor system isdescribed as being a combination of a film-forming agent of polymer typeand a surfactant, with the film-forming agent of polymer type being mostpreferably exemplified by polyvinylpyrrolidone, polyvinyl alcohols, andcopolymers of vinyl acetate and vinylpyrrolidone, and with thesurfactant being most preferably exemplified by polyoxyethylenatedsorbitan esters, and in particular, polysorbate 80. It is believed thatthese crystallization inhibitors act by forming a film matrix which,while possibly allowing small crystals to form, inhibits theirsubsequent growth.

Although pesticidal compositions that include this type ofcrystallization inhibitor system are effective, it has been determinedthat the rate at which ectoparasites such as fleas are eradicated is notoptimal and can be improved by utilizing a different class ofcrystallization inhibitors, particularly those which are notfilm-forming agents of polymer type.

It is therefore the principal object of the present invention to provideectoparasiticidal formulations for the treatment and protection ofcompanion animals having enhanced efficacy.

It is another object of the present invention to provideectoparasiticidal compositions that are easy to use.

It is yet a further object of the present invention to provideectoparasiticidal formulations having a higher rate of kill of parasitesthan can be achieved using presently-available compositions.

SUMMARY OF THE INVENTION

These and other objects of the present invention are achieved byproviding an ectoparasiticidal formulation which surprisingly yields asignificantly enhanced speed of kill. The improved formulation comprisesan ectoparasiticidal agent, preferably fipronil, as thepesticidally-active ingredient, together with a crystallizationinhibitor selected from the group consisting of alkyl-substitutedpyrrolidones, and optionally, one or more organic solvents and/orco-solvents.

The crystallization inhibitor is preferably N-octyl pyrrolidone, and itpreferably comprises from 0.1% to 100% of the ectoparasiticidalcomposition (excluding the active ingredient). Optionally, thecomposition may also include one or more additional solvents, as well asone or more suitable carriers, extenders, and/or excipients.

The methods of the invention comprise methods of parasite control forcompanion animals by administering the improved ectoparasiticidalcompositions to the skin of the animal, preferably in a topical fashion,as a spray-on, stripe on or spot-on formulation.

Thus, one aspect of the present invention generally concerns improvedformulations for treating companion animals suffering from one or moreectoparasitical infestations. One embodiment of this aspect provides aformulation comprising an active ingredient such as fipronil combinedwith a crystallization inhibitor comprising N-octyl pyrrolidone.

Another aspect of the invention generally concerns improved methods fortreating companion animals suffering from one or more ectoparasiticalinfestations. In one embodiment of this aspect of the invention, methodsfor administering an ectoparasiticidal formulation to an infested animalare provided. In another embodiment of this aspect of the invention,methods for manufacturing ectoparasiticidal formulations are provided.

It is a feature of the present invention that the compositions yield akill rate for ectoparasites that is significantly improved as comparedwith the prior art compositions containing the same ectoparasiticidalagent. The kill rate is enhanced not only initially, immediatelyfollowing application to the animal, but a high kill rate is alsomaintained for a longer period of time after the initial treatment thanwith prior art formulations.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The preferred and other embodiments of each aspect of the presentinvention will now be further described.

The present invention resides in the discovery that alkyl-substitutedpyrrolidones, and in particular, N-octyl pyrrolidone, when used in anectoparasiticidal composition in combination with the active ingredientfipronil, facilitates more rapid and sustained activity of the fipronil.Without being bound by any particular explanation, it is believed thatthis enhanced activity is due to the improved solubility of fipronil inN-octyl pyrrolidone, resulting in augmented availability of the activeingredient while it is present on the animal, and enhancing the abilityof fipronil to penetrate the arthropod cuticle, thereby achieving, inturn, more rapid and sustained pesticidal action of the fipronil bydisruption of the insect's central nervous system.

In accordance with one embodiment of the invention, the compositioncomprises fipronil as the pesticidally-active ingredient, in combinationwith the preferred crystallization inhibitor, N-octyl pyrrolidone, alone(i.e., excluding any additional solvents for the pesticidally-activeingredient). In general, the composition should contain an amount offipronil that is between about 1% and about 20% by weight of the overallcomposition, and it should contain an amount of N-octyl pyrrolidone thatis between about 80% and about 99% by weight of the overall composition.

In accordance with another, more preferred embodiment of the invention,the composition comprises fipronil as the pesticidally-activeingredient, in combination with the preferred crystallization inhibitor,N-octyl pyrrolidone, and at least one organic solvent. In general, thiscomposition should contain an amount of fipronil that is between about1% and about 20% by weight of the overall composition, and it shouldcontain an amount of N-octyl pyrrolidone that is between about 1% andabout 90% by weight of the overall composition. The organic solvent maybe present in the overall composition in a percentage by weight whichrepresents the complement of 100% of the composition, given the weightpercentages of fipronil and of N-octyl pyrrolidone that have beenselected.

More preferably, the composition comprises an amount of fipronil that isbetween about 5.0% and about 11.0% by weight of the overall composition,and an amount of N-octyl pyrrolidone that is between about 10% and about20% by weight of the overall composition. Most preferably, thecomposition comprises an amount of fipronil that is about 10% by weightof the overall composition, combined with an amount of N-octylpyrrolidone that is about 15% of the overall composition.

Although N-octyl pyrrolidone is the preferred crystallization inhibitorof the present invention, other alkyl-substituted pyrrolidones can serveas the crystallization inhibitor in other embodiments of the invention.Examples of acceptable alkyl-substituted pyrrolidones include N-methylpyrrolidone and N-dodecyl pyrrolidone. None of these alkyl-substitutedpyrrolidones is a polymer, and none of them is film-forming.

The organic solvent that is selected should have a dielectric constantof between 10 and 35, and preferably between 20 and 30. Among theorganic solvents that may be used, the following are preferred: acetone,benzyl alcohol, butyl diglycol, dipropylene glycol n-butyl ether,ethanol, isopropanol, methanol, ethylene glycol monoethyl ether,ethylene glycol monomethyl ether, dipropylene glycol monoethyl ether,propylene glycol, diethylene glycol monoethyl ether, ethylene glycol,cyclic carbonates and lactones; optionally, a mixture of at least two ofthese solvents may be utilized. Most preferably, the organic solventcomprises diethylene glycol monoethyl ether.

Optionally, the composition may also contain an organic co-solvent,having a boiling point below 100 degrees C., and preferably below 80degrees C., and having a dielectric constant of between 10 and 40, andpreferably between 20 and 30. The organic co-solvent should be volatile,so as to act as a drying promoter, and should be miscible with waterand/or with the organic solvent mentioned above. If an organicco-solvent is included, then the organic solvent and the organicco-solvent may be present in the overall composition in a weightpercentage representing the complement of 100% of the composition, giventhe weight percentages of fipronil and of N-octyl pyrrolidone that havebeen selected. Further, the organic solvent may be present in theoverall composition in a proportion with the organic co-solvent rangingfrom about 1:99 to about 99:1. Among the organic solvents that may beused, the following are preferred: ethanol, isopropanol, and methanol;optionally, more than one of these co-solvents may be utilized. Mostpreferably, the organic co-solvent comprises ethanol.

Optionally, the composition may also contain other additionalingredients, such as carriers, extenders, and/or excipients, one or moreof which may be added for processing and/or aesthetic reasons, as willbe evident to those of skill in the art. Examples of such additionalingredients include carriers or extenders such as safflower oil, cornoil, sesame oil, glycerine, glycols, esters, alcohols, cycliccarbonates, lactones and even water. Safflower oil is a particularlypreferred natural carrier/extender for use with the present invention,since it also helps to solubilize the waxy and oily substances that maybe present on the outer surface of the flea cuticle, thus facilitatingeven further the penetration of the fipronil, and thereby furtherenhancing the speed with which it can act on the insect's centralnervous system.

In general, the compositions of the present invention may be prepared bysimply mixing the constituents together. Preferably, thepesticidally-active ingredient (e.g., fipronil) is added to either asingle liquid ingredient, or to a combination of two or more of theliquid ingredients. The ingredients are mixed by simple stirring untilall of the fipronil has been solubilized. Thereafter, the resultingsolution may be prepared for administration to a companion animal as aconvenient spray-on or spot-on composition, in accordance withtechniques that are well-known to those of ordinary skill in the art.

The following examples of formulations containing fipronil as thepesticidally-active ingredient and N-octyl pyrrolidone as thecrystallization inhibitor are given for purposes of illustration only,and are not intended to be construed as limiting the scope of theinvention in any way.

Example 1

A Formulation I, consistent with the preferred embodiment of theinvention, was prepared by mixing 74.95% by weight of diethylene glycolmonoethyl ether with 15% by weight of N-octyl pyrrolidone, followed byadding 10.05% by weight of technical fipronil and mixing until thefipronil was completely dissolved.

Example 2

A Formulation II, consistent with another embodiment of the invention,was prepared by mixing 66.95% by weight of diethylene glycol monoethylether with 15% by weight of N-octyl pyrrolidone, followed by adding10.05% by weight of technical fipronil and mixing until the fipronil wascompletely dissolved. Thereafter, enough ethanol was added to make up 8%by weight of the overall composition, followed by further mixing tocomplete the formula.

Example 3

A Formulation III, consistent with yet another embodiment of theinvention, was prepared by mixing 72.95% by weight of diethylene glycolmonoethyl ether with 15% by weight of N-octyl pyrrolidone, followed byadding 10.05% by weight of technical fipronil and mixing until thefipronil was completely dissolved. Thereafter, enough safflower oil wasadded to make up 2% by weight of the overall composition, followed byfurther mixing to complete the formula.

In-vivo experimental speed of kill test data, which demonstrate theefficacy of the present invention, as compared with two presentlyavailable commercial ectoparasiticidal products, both of which containfipronil as the pesticidally-active ingredient, are set forth below inTable 1.

Testing was performed on four groups of animals, consisting of eightdogs in each group; weights of the dogs ranged from 9.3 to 48.1 lbs. Onegroup remained untreated as a control, while each of the other threegroups of dogs was assigned for treatment with one of three testproducts.

The test products evaluated included the product commercially availableunder the trademark Pet Armor®, the product commercially available underthe trademark Frontline Top Spot®, and the preferred composition of thepresent invention (using Formulation I prepared in accordance with theforegoing Example 1). All three of these test products contained 9.7%pure fipronil.

On Test day 0, the test products were applied to the test dogs in thethree groups designated for treatment using the following dosages: dogsweighing up to 22 lbs received a 0.67 ml dose, dogs weighing 23-44 lbsreceived a 1.34 ml dose, and dogs weighing 45-88 lbs received a 2.68 mldose. The Pet Armor′) and Frontline Top Spot® test products were appliedusing a spot treatment, as per commercial label instructions, while testproduct comprising the preferred composition of the present inventionwas applied using the stripe treatment which is specified on thecommercial label instructions of the Frontline Top Spot® test product asan acceptable alternative method of application.

One hundred (100) fleas were placed on each test dog 48 hours afterapplication of the test product; the fleas were placed at a locationaway from the test product application site. After two hours of fleaexposure, the test dogs were combed to remove all fleas and to recordthe number of fleas, both alive and dead. The percent flea reduction (%RED.) was calculated based on the test dog flea counts from the treateddogs vs the flea counts from the untreated dogs.

Weekly thereafter, the test dogs were re-infested with fleas, and thenalive fleas were counted after two hours of flea exposure. The percentflea reduction was recorded through four weeks subsequent to applicationof the test product.

TABLE 1 Formulation I Pet Armour ® Frontline ® Day % RED. Fleas % RED.Fleas % RED. Fleas Day 0: Treatment Day 2: Flea Count 2 hour exposure 9478 87 Day 9: Flea Count 2 hour exposure 96 74 81 Day 16: Flea Count 2hour exposure 93 75 71 Day 23: Flea Count 2 hour exposure 91 62 69 Day30: Flea Count 2 hour exposure 61 30 33

The data shown in Table 1 indicate that the percentage kill of fleasobtained with the present invention over a four week period of timegreatly exceeds that obtained in the same amount of time with the twocommercially-available fipronil-containing ectoparasiticidal products.In particular, the formulation of the present invention not onlyprovides a high kill rate immediately following treatment, but it alsomaintains a kill rate that is greater than 90% for three weeks followingthe initial treatment, which is not achieved by the prior artformulations.

Although fipronil is preferred as the pesticidally-active ingredient, itis to be understood that alkyl-substituted pyrrolidones, and inparticular, N-octyl pyrrolidone, may be utilized as a crystallizationinhibitor in combination with other pesticidal ingredients that areknown to be active against ectoparasites, such as other N-phenylpyrazoles (e.g., acetoprole, ethiprole, flufiprole, pyrafluprole,pyriprole, pyrolan, vaniliprole), natural pyrethrins, syntheticpyrethroids (e.g., permethrin, etofenprox, phenothrin, flumethrin,tetramethrin), insect growth regulators (e.g., methoprene, pyriproxifen,dimilin, novaluron, lufneuron, etoxazole), synergists (e.g., PBO,n-octyl bicycloheptene dicarboximide), organophosphates, carbamates,diamides (excluding specifically chlorantraniliprole andcyantraniliprole), oxadiazines (e.g., indoxacarb), macrocyclic lactones(e.g., avermectins), formamidines (e.g., amitraz), biopesticides andbotanical extracts, so as to deter their re-crystallization and therebyenhance their speed of kill as well. Compositions comprising analkyl-substituted pyrrolidone together with one or more of these otherpesticidally-active ingredients may further include, if necessary ordesirable, suitable stabilizers such as, for example, butylhydroxytoluene (BHT). However, neonicotinoids (e.g., imidacloprid,thiacloprid, dinotefuan, thiamethoxam) is a class of pesticidally-activeingredients that, even though known to be active against ectoparasites,are specifically excluded from the scope of the present invention.

While there has been described what are at present considered to be thepreferred embodiments of the present invention, it will be apparent tothose skilled in the art that the embodiments described herein are byway of illustration and not of limitation. Various modifications of thedisclosed embodiments, as well as alternative embodiments of theinvention, will become apparent to persons skilled in the art uponreference to the description of the invention. Therefore, it is to beunderstood that various changes and modifications may be made in theembodiments disclosed herein without departing from the true spirit andscope of the present invention, as set forth in the appended claims, andit is contemplated that the appended claims will cover any suchmodifications or embodiments.

1. A method of treating an animal infested with ectoparasites, themethod comprising topically applying to the animal's body an effectiveamount of a composition comprising (a) an ectoparasiticidal agent and(b) a crystallization inhibitor selected from the group consisting ofalkyl-substituted pyrrolidones, said composition excluding anyadditional solvents for the ectoparasiticidal agent and saidectoparasiticidal agent excluding neonicotinoids and excludingchlorantraniliprole and cyantraniliprole.
 2. A method of treating ananimal infested with ectoparasites, the method comprising topicallyapplying to the animal's body an effective amount of a compositioncomprising (a) an ectoparasiticidal agent selected from the groupconsisting of N-phenyl pyrazoles, natural pyrethrins, syntheticpyrethroids, insect growth regulators, synergists, organophosphates,carbamates, diamides excluding chlorantraniliprole and cyantraniliprole,oxadiazines, macrocyclic lactones, formamidines, biopesticides andbotanical extracts, (b) a crystallization inhibitor selected from thegroup consisting of N-methyl pyrrolidone, N-octyl pyrrolidone, andN-dodecyl pyrrolidone, and (c) at least one organic solvent.
 3. Themethod of claim 2 wherein said ectoparasiticidal agent is the N-phenylpyrazole whose common name is fipronil, and wherein said crystallizationinhibitor is N-octyl pyrrolidone.
 4. The method of claim 3 wherein saidanimal is a domestic companion animal, and said ectoparasites are fleas.5. The method of claim 4 wherein said domestic companion animal is adog.
 6. The method of claim 4 wherein said domestic companion animal isa cat.
 7. A method for controlling an ectoparasite infestation on ananimal, the method comprising topically applying to a localized regionof the animal's body an effective amount of a composition comprising anectoparasiticidal agent which is the N-phenyl pyrazole whose common nameis fipronil, a crystallization inhibitor which is N-octyl pyrrolidone,and at least one organic solvent.
 8. The method of claim 7 wherein saidanimal is a dog, and said ectoparasite is a flea.
 9. The method of claim7 wherein said animal is a cat, and said ectoparasite is a flea.
 10. Amethod for controlling an ectoparasite infestation on an animal, themethod comprising topically applying to the animal's body an effectiveamount of a composition comprising (a) an ectoparasiticidal agent whichis the N-phenyl pyrazole whose common name is fipronil, (b) acrystallization inhibitor selected from the group consisting of N-methylpyrrolidone, N-octyl pyrrolidone, and N-dodecyl pyrrolidone, and (c) atleast one organic solvent, wherein said ectoparasiticidal agent ispresent in an amount comprising from about 1% to about 20% by weight ofthe overall composition, and wherein said crystallization inhibitor ispresent in an amount comprising from about 1% to about 90% by weight ofthe overall composition.
 11. The method of claim 10 wherein saidcrystallization inhibitor is N-octyl pyrrolidone.
 12. The method ofclaim 11 wherein said at least one organic solvent is selected from thegroup consisting of acetone, benzyl alcohol, butyl diglycol, dipropyleneglycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycolmonoethyl ether, ethylene glycol monomethyl ether, dipropylene glycolmonoethyl ether, propylene glycol, diethylene glycol monoethyl ether,ethylene glycol, cyclic carbonates, lactones, and mixtures of at leasttwo of said solvents.
 13. The method of claim 12 wherein said at leastone organic solvent comprises diethylene glycol monoethyl ether.
 14. Themethod of claim 13 wherein said ectoparasiticidal agent is present in anamount comprising from about 7.0% to about 11.0% by weight of theoverall composition, and wherein said crystallization inhibitor ispresent in an amount comprising from about 10% to about 20% by weight ofthe overall composition.
 15. The method of claim 14 wherein saidectoparasiticidal agent is present in an amount comprising about 10.0%by weight of the overall composition, and wherein said crystallizationinhibitor is present in an amount comprising about 15% by weight of theoverall composition.
 16. The method of claim 15 wherein said compositionfurther comprises at least one organic co-solvent selected from thegroup consisting of ethanol, isopropanol, and methanol, and wherein saidat least one organic solvent and said at least one organic co-solventare present in an amount by weight which represents the complement of100% of the overall composition and said at least one organic solvent ispresent in a proportion with said at least one organic co-solventranging from about 1:99 to about 99:1.
 17. The method of claim 16wherein said organic solvent is present in an amount comprising about67% by weight of the overall composition and said organic co-solvent ispresent in an amount comprising about 8% by weight of the overallcomposition, and wherein said at least one organic co-solvent comprisesethanol.
 18. The method of claim 17 wherein said animal is a domesticcompanion animal selected from the group consisting of dogs and cats,and said ectoparasites are fleas.
 19. The method of claim 15 whereinsaid composition further comprises at least one carrier or extenderselected from the group consisting of safflower oil, corn oil, sesameoil, glycerine, glycols, esters, alcohols, cyclic carbonates, lactonesand water.
 20. The method of claim 19 wherein said organic solvent ispresent in an amount comprising about 73% by weight of the overallcomposition and said at least one carrier or extender is present in anamount comprising about 2% by weight of the overall composition, andwherein said at least one carrier or extender comprises safflower oil.21. The method of claim 20 wherein said animal is a domestic companionanimal selected from the group consisting of dogs and cats, and saidectoparasites are fleas.
 22. The method of claim 2 wherein saidectoparasiticidal agent comprises at least one insect growth regulator,and wherein said composition further comprises a stabilizer.
 23. Themethod of claim 22 wherein said stabilizer comprises butylhydroxytoluene.